Lioresal Intrathecal

Drug Substance

Baclofen

Chemical Name: 4-amino-3-(p-chlorophenyl) butyric acid

Molecular Formula: C10H12ClNO2

Molecular Weight: 213.67

Description: White to off-white, odorless or practically odorless crystalline powder.

Solubility: Slightly soluble in water, very slightly soluble in methanol and insoluble in chloroform.  

pKa: pKa, 1 = 3.87 (carboxyl group) and pKa, 2 = 9.62 (amino group) in water at 20OC.

Composition

The contents of each sterile ampoule are described in the following table.

The precise mechanisms of action of LIORESAL (baclofen) as an antispastic agent are not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflex transmission at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals. Actions at supraspinal sites may also contribute to its clinical effect. Baclofen is an analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype.

Baclofen has been shown to have general Central Nervous System (CNS) depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia and respiratory and cardiovascular depression.

In neurological diseases associated with spasm of the skeletal muscles, LIORESAL Intrathecal may have beneficial action on reflex muscle contractions, painful spasm, automatism, hyperreflexia, trismus and clonus. Neuromuscular transmission is not affected by baclofen. Baclofen may also reduce pain associated with spasticity.

Pharmacodynamics of LIORESAL Intrathecal

The onset of action is generally half an hour to one hour after administration of an intrathecal bolus dose. Peak antispastic effect is seen at approximately 4 hours after dosing and effects may last 4 to 8 hours. Onset, peak response, and duration of action vary with individual patients depending on the dose and severity of symptoms.

The antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum efficacy is observed in 24 to 48 hours.

Pharmacokinetics of LIORESAL Intrathecal

After LIORESAL Intrathecal administration, the concentration of baclofen in the Cerebrospinal Fluid (CSF) is approximately 100 times higher than what is found following oral administration.

Because of slow CSF circulation and a baclofen concentration gradient from the lumbar to the cisternal CSF, the pharmacokinetic parameters as described below should be interpreted considering a high inter- and intra-patient variability.

The clearance of intrathecal baclofen, calculated from intrathecal bolus or continuous infusion studies, approximate its CSF turnover, suggesting elimination via bulk-flow removal of CSF. Direct infusion into the spinal subarachnoid space bypasses absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord.

After a bolus lumbar injection of 50 or 100 μg LIORESAL Intrathecal in 7 patients, the average CSF elimination half-life was 1.51 hours over the first four hours and the average CSF clearance was approximately 30 mL/hour. After single intrathecal bolus injection/short-term infusion, the volume of distribution in intrathecal compartment, calculated from CSF levels, ranges from 22 to 157 mL.

A study, conducted in 10 patients, suggests that the mean CSF clearance for continuous intrathecal infusion of LIORESAL is approximately 30 mL/hour.

Continuous intrathecal infusion daily doses of 50 to 1200 μg result in lumbar CSF concentrations of baclofen as high as 130 to 1240 ng/mL at steady state. According to the half-life measured in the CSF, CSF steady state concentrations will be reached within 1-2 days. During Intrathecal infusion the plasma concentrations do not exceed 5 ng/mL.

Limited pharmacokinetic data suggest that a lumbar-cisternal baclofen concentration gradient of about 4:1 is established during continuous baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap during continuous baclofen infusion at the lumbar level in doses associated with therapeutic efficacy. The interpatient variability was considerable. This gradient suggests that spasticity in the lower extremities may be relieved with little effect on the upper limbs and with fewer cerebral adverse reactions due to diminished effects on the brain.

Special populations

No pharmacokinetic data is available in elderly patients after administration of LIORESAL Intrathecal. When a single dose of the oral formulation is administered, data suggest that elderly patients have a slower rate of absorption and elimination, a slightly prolonged elimination half-life, but a similar systemic exposure to baclofen compared to young adults.

No pharmacokinetic data is available in patients with hepatic impairment after administration of LIORESAL Intrathecal. However, as the liver does not play a significant role in the disposition of baclofen it is unlikely that its pharmacokinetics would be altered to a clinically significant level in patient with hepatic impairment.

No pharmacokinetic data is available in patients with renal impairment after administration of LIORESAL Intrathecal. Since baclofen is primarily eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment cannot be excluded. Severe neurological outcomes have been reported in patients with renal impairment after oral administration, thus LIORESAL Intrathecal should be given with special care and caution in these patients (see PRECAUTIONS, Renal Impairment).

Pharmacology

Baclofen depresses monosynaptic and polysynaptic reflex transmission in the spinal cord. The antispastic activity is derived primarily from its action at the spinal level to reduce spasms in voluntary muscles (see also LIORESAL Product Monograph).

Intrathecal baclofen exerts an antinociceptive effect in rats and cats. These effects are independent of any debilitation of voluntary motor function. In addition, intrathecal baclofen affects lower urinary tract dynamics of the anesthetized dog. Vesical and urethral pressure was significantly decreased. Within 30 minutes of injection, relaxation of the bladder and a reduction in urethral resistance occurred.

Toxicology

LD50 values following intrathecal dosing are not available.

The oral toxicity of LIORESAL has been thoroughly investigated. LIORESAL Intrathecal requires the use of much smaller doses to achieve a therapeutic effect, with consequential lower systemic exposure.

Repeated intrathecal administration of baclofen to rats and dogs was not associated with irritation or inflammation of the spinal cord and surrounding tissues. Inflammation of the spinal cord was observed in one rabbit in a study that administered intrathecal baclofen to 3 rabbits weekly over a period of 3 to 6 months.

Subacute and subchronic studies with continuous intrathecal baclofen infusion in two species (rat, dog) revealed no signs of local irritation or inflammation on histological examination. Preclinical studies in animal models have demonstrated that the formation of inflammatory mass is directly related to high dose and/or high concentration of intrathecal opioids and no inflammatory mass is formed with intrathecal baclofen as a sole agent.

Oral baclofen showed no significant adverse effects on fertility or postnatal development at non-maternally toxic dose levels in rats (approximately 2.1-times the maximum oral mg/kg dose in adults). At maternally toxic dose levels (8.3-times the maximum oral mg/kg dose in adults), baclofen increased the the incidence of omphalocoeles (ventral hernias) in rats, an effect not seen in mice or rabbits. Delayed fetal growth (ossification of bones) in the fetuses of rats and rabbits was also observed at maternotoxic doses.

Rat: Doses of 4.4-5 and 17.7-21.3 mg/kg/day were administered orally to two groups of female rats during pre-mating, mating, gestation and lactation. The only significant effect was a reduction in litter size and survivability of offspring (possibly due to agalactia) in the high dose group. In another rat study, doses of 5 and 10 mg/kg/day were administered by gavage during the last trimester of pregnancy and throughout the lactation period. Five of 31 dams in the high dose group showed severe weight loss from days 15-21 of gestation as well as agalactia and the entire litter of each of these dams died by day 2 postpartum. In a third study, baclofen doses of 30 mg/kg/day produces symptoms of ataxia and drowsiness in dams and the death of 4 of 24 dams dosed from gestation Days 1 to 12. At this high dose level, there was a slight increase in the resorption rate; however, the number and size of the fetuses remained normal and no malformations were reported.

Rat and Mouse: Doses of 5 and 20 mg/kg/day were administered by gavage to two groups of pregnant rats on days 6-15 of gestation. The only significant finding was the presence of abdominal hernias in 4/160 fetuses in the high dose group. In a second similar study, 1/229 control fetuses and 2/293 fetuses from dams receiving 20 mg/kg/day had abdominal hernias (See also WARNINGS). Comparable lesions did not occur in a similar mouse study.

The average number of stillbirths or viable newborns did not differ significantly between control and medicated groups. The average weight of neonates from the high dose group was significantly reduced.

Rabbit: Doses of 1, 5 and 10 mg/kg/day were administered by gavage to groups of rabbits from the 6th to 18th day of gestation. There was an increased incidence of unossified phalangeal nuclei of forelimbs and hindlimbs in the fetuses from the high dose group. In another study, a slight increase in resorption rates was observed in rabbits receiving 10 and 15 mg/kg/day of oral baclofen.

Baclofen did not cause teratogenic effects in mice, rats, and rabbits at doses up to125-times the maximum intrathecal mg/kg dose. LIORESAL given orally increased the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 500-times the maximum intrathecal dose expressed as a mg/kg dose. This abnormality was not seen in mice or rabbits. LIORESAL dosed orally caused delayed fetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits, and when given intraperitoneally, baclofen at high doses caused widening of the vertebral arch in rat fetuses.

A 2-year rat study (oral administration) showed that baclofen is not carcinogenic. In the same study a dose-related increase in incidence of ovarian cysts and a less marked increase in enlarged and/or hemorrhagic adrenal glands was observed.

Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters.

References

DELHAAS EM, and BROUWERS JRBJ. Intrathecal baclofen overdose: report of 7 events in 5 patients and review of the literature. Int J Clin Pharmacol Ther Toxicol 1991; 29: 274-280

LAZORTHES Y, SALLERIN-CAUTE B, VERDIE J-C, BASTIDE R, and CARILLO J-P. Chronic intrathecal baclofen administration for control of severe spasticity. J Neurosurg 1990; 72: 393-402

McLEAN BN. Intrathecal baclofen in severe spasticity. Br J Hosp Med 1993; 49 (4): 262-267

MÜLLER H, ZIERSKI J, DRALLE D, KRAUSS D, and MUTSCHLER E. Pharmacokinetics of intrathecal baclofen. IN: Müller H, Zierski J, and Penn RD (eds). Local-spinal therapy of spasticity. Springer-Verlag, Berlin etc., 1988; pp 223-226

MÜLLER H, ZIERSKI J, DRALLE D, HOFFMANN O, and MICHAELIS G. Intrathecal baclofen in spasticity. IN: Müller H, Zierski J, and Penn RD (eds). Local-spinal therapy of spasticity. Springer-Verlag, Berlin, etc.,1988; pp 155-214

OCHS G. Intrathecal baclofen for long-term treatment of spasticity: a multi-centre study. J Neurol Neurosurg Psychiatry 1989; 52: 933-939

PARKE B, PENN RD, SAVOY SM and CORCOS D. Functional outcome after delivery of intrathecal baclofen. Arch Phys Med Rehabil 1989; 70: 30-32

PENN RD. Intrathecal baclofen for severe spasticity. Ann NY Acad Sci 1988; 531: 157-166

PENN RD, SAVOY SM, CORCOS D, LATASH M, GOTTLIER G, PARKE B, and KROIN JS. Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989; 320: 1517-1521

PENN RD, and KROIN JS. Long-term intrathecal baclofen infusion for treatment of spasticity. J Neurosurg 1987; 66: 181-185

• Gablofen
• Lyrica
• Neurontin

• Savella
• Ultracet

© Lioresal Intrathecal Patient Information is supplied by Cerner Multum, Inc. and Lioresal Intrathecal Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

In the U.S.

• Gablofen
• Lioresal

Available Dosage Forms:

• Solution
• Kit

Therapeutic Class: Skeletal Muscle Relaxant, Centrally Acting

Chemical Class: Gamma Aminobutyric Acid (class)

Intrathecal baclofen is used to help relax certain muscles in your body. It relieves the spasms, cramping, and tightness of muscles caused by medical problems such as multiple sclerosis, cerebral palsy, or certain injuries to the spine. Intrathecal baclofen does not cure these problems, but it may allow other treatment, such as physical therapy, to be more helpful in improving your condition.

Intrathecal baclofen acts on the central nervous system (CNS) to produce its muscle relaxant effects. Its actions on the CNS may also cause some of the medicine's side effects.

This medicine is delivered by a drug pump directly into the spinal fluid of your back. A doctor will surgically place the pump and monitor the dose of the medication that is delivered by the pump. The dose of intrathecal baclofen will be different for different patients and will depend on the type of muscle tightness that you have.

Intrathecal baclofen is given only by or under the direct supervision of a doctor.

Lioresal Intrathecal is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) and in implantable pumps approved by the FDA specifically for the intrathecal administration of baclofen. Because of the possibility of potentially life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure, physicians must be adequately trained and educated in chronic intrathecal infusion therapy.

The pump system should not be implanted until the patient's response to bolus Lioresal Intrathecal injection is adequately evaluated. Evaluation (consisting of a screening procedure: see Dosage and Administration) requires that Lioresal Intrathecal be administered into the intrathecal space via a catheter or lumbar puncture. Because of the risks associated with the screening procedure and the adjustment of dosage following pump implantation, these phases must be conducted in a medically supervised and adequately equipped environment following the instructions outlined in the Dosage and Administration section.

Resuscitative equipment should be available.

Following surgical implantation of the pump, particularly during the initial phases of pump use, the patient should be monitored closely until it is certain that the patient's response to the infusion is acceptable and reasonably stable.

On each occasion that the dosing rate of the pump and/or the concentration of Lioresal Intrathecal (baclofen injection) in the reservoir is adjusted, close medical monitoring is required until it is certain that the patient's response to the infusion is acceptable and reasonably stable.

It is mandatory that the patient, all patient caregivers, and the physicians responsible for the patient receive adequate information regarding the risks of this mode of treatment. All medical personnel and caregivers should be instructed in 1) the signs and symptoms of overdose, 2) procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site.

Overdose

Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction, inadvertent subcutaneous injection, or dosing error. (See Drug Overdose Symptoms and Treatment.)

Extreme caution must be used when filling an FDA approved implantable pump. Such pumps should only be refilled through the reservoir refill septum. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Some pumps are also equipped with a catheter access port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port or inadvertent injection into the subcutaneous tissue may cause a life-threatening overdose.

Withdrawal

Abrupt withdrawal of intrathecal baclofen, regardless of the cause, has resulted in sequelae that included high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that in rare cases progressed to rhabdomyolysis, multiple organ-system failure, and death. In the first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six patients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Common reasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir, and end of pump battery life; human error may have played a causal or contributing role in some cases. Cases of intrathecal mass at the tip of the implanted catheter leading to withdrawal symptoms have also been reported, most of them involving pharmacy compounded analgesic admixtures (see PRECAUTIONS).

Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal.

All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal. Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias. Priapism may develop or recur if treatment with intrathecal baclofen is interrupted. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.

Rapid, accurate diagnosis and treatment in an emergency-room or intensive-care setting are important in order to prevent the potentially life-threatening central nervous system and systemic effects of intrathecal baclofen withdrawal. The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist drugs such as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.

Seizures have been reported during overdose and with withdrawal from Lioresal Intrathecal as well as in patients maintained on therapeutic doses of Lioresal Intrathecal.

Fatalities

There were 16 deaths reported among the 576 U.S. patients treated with Lioresal Intrathecal (baclofen injection) in pre- and post- marketing studies evaluated as of December 1992. Because these patients were treated under uncontrolled clinical settings, it is impossible to determine definitively what role, if any, Lioresal Intrathecal played in their deaths.

As a group, the patients who died were relatively young (mean age was 47 with a range from 25 to 63), but the majority suffered from severe spasticity of many years duration, were nonambulatory, had various medical complications such as pneumonia, urinary tract infections, and decubiti, and/or had received multiple concomitant medications. A case-by-case review of the clinical course of the 16 patients who died failed to reveal any unique signs, symptoms, or laboratory results that would suggest that treatment with Lioresal Intrathecal caused their deaths. Two patients, however, did suffer sudden and unexpected death within 2 weeks of pump implantation and one patient died unexpectedly after screening.

One patient, a 44 year old male with MS, died in hospital on the second day following pump implantation. An autopsy demonstrated severe fibrosis of the coronary conduction system. A second patient, a 52 year old woman with MS and a history of an inferior wall myocardial infarction, was found dead in bed 12 days after pump implantation, 2 hours after having had documented normal vital signs. An autopsy revealed pulmonary congestion and bilateral pleural effusions. It is impossible to determine whether Lioresal Intrathecal contributed to these deaths. The third patient underwent three baclofen screening trials. His medical history included SCI, aspiration pneumonia, septic shock, disseminated intravascular coagulopathy, severe metabolic acidosis, hepatic toxicity, and status epilepticus. Twelve days after screening (he was not implanted), he again experienced status epilepticus with subsequent significant neurological deterioration. Based upon prior instruction, extraordinary resuscitative measures were not pursued and the patient died.

There were three deaths occurring among the 211 patients treated with Lioresal Intrathecal in pre- marketing studies as of March 1996. These deaths were not attributed to the therapy.

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer's manual for specific recommendations.

Safety and effectiveness in pediatric patients below the age of 4 have not been established.

Screening

Patients should be infection-free prior to the screening trial with Lioresal Intrathecal (baclofen injection) because the presence of a systemic infection may interfere with an assessment of the patient's response to bolus Lioresal Intrathecal.

Pump Implantation

Patients should be infection-free prior to pump implantation because the presence of infection may increase the risk of surgical complications. Moreover, a systemic infection may complicate dosing.

Pump Dose Adjustment and Titration

In most patients, it will be necessary to increase the dose gradually over time to maintain effectiveness; a sudden requirement for substantial dose escalation typically indicates a catheter complication (i. e., catheter kink or dislodgement).

Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Subcutaneous injection may result in symptoms of a systemic overdose or early depletion of the reservoir. Refill intervals should be carefully calculated to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possibly symptoms of withdrawal.

Strict aseptic technique in filling is required to avoid bacterial contamination and serious infection. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir.

Extreme caution must be used when filling an FDA approved implantable pump equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the catheter access port may cause a life-threatening overdose.

It may be important to titrate the dose to maintain some degree of muscle tone and allow occasional spasms to: 1) help support circulatory function, 2) possibly prevent the formation of deep vein thrombosis, 3) optimize activities of daily living and ease of care.

Except in overdose related emergencies, the dose of Lioresal Intrathecal should ordinarily be reduced slowly if the drug is discontinued for any reason.

An attempt should be made to discontinue concomitant oral antispasticity medication to avoid possible overdose or adverse drug interactions, either prior to screening or following implant and initiation of chronic Lioresal Intrathecal infusion. Reduction and discontinuation of oral anti-spasmotics should be done slowly and with careful monitoring by the physician. Abrupt reduction or discontinuation of concomitant antispastics should be avoided.

Drowsiness

Drowsiness has been reported in patients on Lioresal Intrathecal. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system depressant effects of Lioresal Intrathecal (baclofen injection) may be additive to those of alcohol and other CNS depressants.

Intrathecal mass

Cases of intrathecal mass at the tip of the implanted catheter have been reported, most of them involving pharmacy compounded analgesic admixtures. The most frequent symptoms associated with intrathecal mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. In patients with new neurological signs or symptoms suggestive of an intrathecal mass, consider a neurosurgical consultation, since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an intrathecal mass.

Precautions in special patient populations

Careful dose titration of Lioresal Intrathecal is needed when spasticity is necessary to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function and care.

Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with Lioresal Intrathecal and kept under careful surveillance, because exacerbations of these conditions have been observed with oral administration.

Lioresal Intrathecal should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of Lioresal Intrathecal (baclofen injection) may cause an autonomic dysreflexic episode.

Because LIORESAL is primarily excreted unchanged by the kidneys, it should be given with caution in patients with impaired renal function and it may be necessary to reduce the dosage.

LABORATORY TESTS

No specific laboratory tests are deemed essential for the management of patients on Lioresal Intrathecal.

DRUG INTERACTIONS

There is inadequate systematic experience with the use of Lioresal Intrathecal in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of Lioresal Intrathecal and epidural morphine include hypotension and dyspnea.

CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY

No increase in tumors was seen in rats receiving baclofen orally for two years. Adequate genotoxicity assays of baclofen have not been performed.

PREGNANCY

There are no adequate and well-controlled studies in pregnant women. In animal studies, baclofen had adverse effects on embryofetal development when administered orally to pregnant rats. Lioresal Intrathecal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Baclofen given orally increased the incidence of fetal structural abnormalities (omphaloceles) in rats. Reductions in food intake and body weight gain were observed in the dams. Fetal structural abnormalities were not observed in mice or rabbits

NURSING MOTHERS

In mothers treated with oral LIORESAL (baclofen USP) in therapeutic doses, the active substance passes into the milk. It is not known whether detectable levels of drug are present in milk of nursing mothers receiving Lioresal Intrathecal. As a general rule, nursing should be undertaken while a patient is receiving Lioresal Intrathecal only if the potential benefit justifies the potential risks to the infant.

PEDIATRIC USE

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer's manual for specific recommendations.

Safety and effectiveness in pediatric patients below the age of 4 have not been established.

Considerations based on experience with oral LIORESAL (baclofen USP)

A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral LIORESAL. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral LIORESAL for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population.

Spasticity of Spinal Cord Origin

Commonly Observed in Patients with Spasticity of Spinal Origin

In pre- and post- marketing clinical trials, the most commonly observed adverse events associated with use of Lioresal Intrathecal (baclofen injection) which were not seen at an equivalent incidence among placebo-treated patients were: somnolence, dizziness, nausea, hypotension, headache, convulsions and hypotonia.

Associated with Discontinuation of Treatment

8/474 patients with spasticity of spinal cord origin receiving long term infusion of Lioresal Intrathecal in pre- and post- marketing clinical studies in the U. S. discontinued treatment due to adverse events. These include: pump pocket infections (3), meningitis (2), wound dehiscence (1), gynecological fibroids (1) and pump overpressurization (1) with unknown, if any, sequela. Eleven patients who developed coma secondary to overdose had their treatment temporarily suspended, but all were subsequently re-started and were not, therefore, considered to be true discontinuations.

Fatalities

See Warnings.

Incidence in Controlled Trials

Experience with Lioresal Intrathecal (baclofen injection) obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies were of very brief duration (up to three days of infusion) and involved only a total of 63 patients. The following events occurred among the 31 patients receiving Lioresal Intrathecal (baclofen injection) in two randomized, placebo-controlled trials: hypotension (2), dizziness (2), headache (2), dyspnea (1). No adverse events were reported among the 32 patients receiving placebo in these studies.

Events Observed during the Pre- and Post-marketing Evaluation of Lioresal Intrathecal

Adverse events associated with the use of Lioresal Intrathecal reflect experience gained with 576 patients followed prospectively in the United States. They received Lioresal Intrathecal for periods of one day (screening) (N = 576) to over eight years (maintenance) (N = 10). The usual screening bolus dose administered prior to pump implantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of Lioresal Intrathecal cannot be reliably assessed in many cases and many of the adverse events reported are known to occur in association with the underlying conditions being treated. Nonetheless, many of the more commonly reported reactions hypotonia, somnolence, dizziness, paresthesia, nausea/vomiting and headache appear clearly drug-related.

Adverse experiences reported during all U.S. studies (both controlled and uncontrolled) are shown in the following table. Eight of 474 patients who received chronic infusion via implanted pumps had adverse experiences which led to a discontinuation of long term treatment in the pre- and post-marketing studies.

In addition to the more common (1% or more) adverse events reported in the prospectively followed 576 domestic patients in pre- and post-marketing studies, experience from an additional 194 patients exposed to Lioresal Intrathecal (baclofen injection) from foreign studies has been reported. The following adverse events, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported:

Nervous System: Abnormal gait, thinking abnormal, tremor, amnesia, twitching, vasodilitation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependence, incoordination, paranoid reaction and ptosis.

Digestive System: Flatulence, dysphagia, dyspepsia and gastroenteritis.

Cardiovascular: Postural hypotension, bradycardia, palpitations, syncope, arrhythmia ventricular, deep thrombophlebitis, pallor and tachycardia.

Respiratory: Respiratory disorder, aspiration pneumonia, hyperventilation, pulmonary embolus and rhinitis.

Urogenital: Hematuria and kidney failure.

Skin and Appendages: Alopecia and sweating.

Metabolic and Nutritional Disorders: Weight loss, albuminuria, dehydration and hyperglycemia.

Special Senses: Abnormal vision, abnormality of accommodation, photophobia, taste loss and tinnitus.

Body as a Whole: Suicide, lack of drug effect, abdominal pain, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome and overdose.

Hemic and Lymphatic System: Anemia.

Spasticity of Cerebral Origin

Commonly Observed

In pre-marketing clinical trials, the most commonly observed adverse events associated with use of Lioresal Intrathecal (baclofen injection) which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia.

Associated with Discontinuation of Treatment

Nine of 211 patients receiving Lioresal Intrathecal in pre-marketing clinical studies in the U.S. discontinued long term infusion due to adverse events associated with intrathecal therapy.

The nine adverse events leading to discontinuation were: infection (3), CSF leaks (2), meningitis (2), drainage (1), and unmanageable trunk control (1).

Fatalities

Three deaths, none of which were attributed to Lioresal Intrathecal, were reported in patients in clinical trials involving patients with spasticity of cerebral origin. See Warnings on other deaths reported in spinal spasticity patients.

Incidence in Controlled Trials

Experience with Lioresal Intrathecal (baclofen injection) obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following events occurred among the 62 patients receiving Lioresal Intrathecal in two randomized, placebo-controlled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolence, leukocytosis, nausea, vomiting, nystagmus, chills, urinary retention, and hypotonia.

Events Observed during the Pre-marketing Evaluation of Lioresal Intrathecal

Adverse events associated with the use of Lioresal Intrathecal reflect experience gained with a total of 211 U. S. patients with spasticity of cerebral origin, of whom 112 were pediatric patients (under age 16 at enrollment). They received Lioresal Intrathecal for periods of one day (screening) (N= 211) to 84 months (maintenance) (N= 1). The usual screening bolus dose administered prior to pump implantation in these studies was 50-75 mcg. The maintenance dose ranged from 22 mcg to 1400 mcg per day. Doses used in this patient population for long term infusion are generally lower than those required for patients with spasticity of spinal cord origin.

Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of Lioresal Intrathecal cannot be reliably assessed in many cases. Nonetheless, many of the more commonly reported reactions somnolence, dizziness, headache, nausea, hypotension, hypotonia and coma appear clearly drug-related.

The most frequent (≥1%) adverse events reported during all clinical trials are shown in the following table. Nine patients discontinued long term treatment due to adverse events.

The more common (1% or more) adverse events reported in the prospectively followed 211 patients exposed to Lioresal Intrathecal (baclofen injection) have been reported. In the total cohort, the following adverse events, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported:

Nervous System: Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, hallucinations, hysteria, insomnia, nystagmus, personality disorder, reflexes decreased, and vasodilitation.

Digestive System: Dysphagia, fecal incontinence, gastrointestinal hemorrhage and tongue disorder.

Cardiovascular: Bradycardia.

Respiratory: Apnea, dyspnea and hyperventilation.

Urogenital: Abnormal ejaculation, kidney calculus, oliguria and vaginitis.

Skin and Appendages: Rash, sweating, alopecia, contact dermatitis and skin ulcer.

Special Senses: Abnormality of accommodation.

Body as a Whole: Death, fever, abdominal pain, carcinoma, malaise and hypothermia.

Hemic and Lymphatic System: Leukocytosis and petechial rash.

Postmarketing Experience

The following adverse events have been reported during post-approval use of Lioresal Intrathecal. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.

The onset of scoliosis or worsening of a pre-existing scoliosis has been reported.

Sexual dysfunction in men and women, including decreased libido and orgasm dysfunction, have been reported. Erectile dysfunction in men has also been reported. Priapism has been reported following baclofen withdrawal.

Lioresal® Intrathecal
(baclofen injection)

10 mg/20 mL
(500 mcg/mL)

Sterile solution for intrathecal injection.
Distributed by Saol Therapeutics Inc.,
Roswell, GA 30076

NDC 70257-560-20
68947 01
LA56002

LOT

EXP

Applies to baclofen: compounding powder, intrathecal solution, oral suspension, oral tablet

Cardiovascular

Common (1% to 10%): Cardiac output decreased, hypotension, hypertension, diminished cardiovascular functions, peripheral edema
Rare (less than 0.1%): Arrhythmias, palpitations, chest pain
Frequency not reported: Bradycardia, orthostatic hypotension[Ref]

Dermatologic

Common (1% to 10%): Rash, hyperhidrosis, urticaria/pruritus, facial edema
Uncommon (0.1% to 1%): Alopecia, diaphoresis
Frequency not reported: Rash, sweating, contact dermatitis, skin ulcer[Ref]

Endocrine

Common (1% to 10%): Ovarian cysts are palpable in 4% of women treated with for up to one year[Ref]

Gastrointestinal

Very common (10% or more): Nausea (especially at start of therapy) (up to 11%)
Common (1% to 10%): Dry mouth, GI disorder/disturbance, constipation, diarrhea, retching, vomiting, increased salivation
Uncommon (0.1% to 1%): Dysphagia, dehydration, ileus, decreased taste sensation
Rare (less than 0.1%): Colicky abdominal pain, anorexia
Frequency not reported: GI hemorrhage[Ref]

Genitourinary

Very common (10% or more): Urinary retention (up to 12%)
Common (1% to 10%): Urinary incontinence, urination impaired, sexual dysfunction, urinary frequency, enuresis, dysuria
Rare (less than 0.1%): Erectile dysfunction
Frequency not reported: Dysuria, abnormal ejaculation, oliguria, vaginitis[Ref]

Hematologic

Frequency not reported: Leukocytosis, petechial rash[Ref]

Hepatic

Rare (less than 0.1%): Disorders of hepatic function (e.g., increased AST)[Ref]

Immunologic

Common (1% to 10%): Pneumonia
Uncommon (0.1% to 1%): Septicemia[Ref]

Metabolic

Common (1% to 10%): Decreased appetite
Frequency not reported: Blood glucose increased[Ref]

Musculoskeletal

Very common (10% or more): Hypotonia (up to 52%), lower extremity weakness (up to 15%), disturbances of gait and balance
Common (1% to 10%): Muscular weakness, myalgia, upper extremity weakness, back pain, muscular hypertonia[Ref]

Nervous system

Very common (10% or more): Somnolence (up to 28%), drowsiness (up to 18%), headache (up to 16%), seizures (especially on discontinuation of therapy) (up to 15%), sedation, dizziness (up to 12%)
Common (1% to 10%): Fatigue, ataxia, tremor, lightheadedness, lassitude, exhaustion, numbness/itching/tingling, slurred speech, lethargy, hypertonia, paresthesia
Rare (less than 0.1%): Dysarthria, dysgeusia, syncope, dyskinesia, coma, potentially life-threatening withdrawal symptoms (as a result of sudden interruption of drug delivery)[Ref]

Other

Common (1% to 10%): Tinnitus, pain, asthenia
Uncommon (0.1% to 1%): Accidental injury, weight loss
Very rare (less than 0.01%): Hypothermia
Frequency not reported: Drug withdrawal syndrome
Uncommon (0.1% to 1%): Subdural hemorrhage, accidental injury, weight loss[Ref]

Ocular

Common (1% to 10%): Nystagmus, visual impairment, accommodation disorder, blurred vision, double vision, amblyopia[Ref]

Psychiatric

Common (1% to 10%): Confusional state, hallucination, depression, insomnia, euphoric mood, nightmare, personality changes
Uncommon (0.1% to 1%): Memory loss/impairment, suicidal ideation, attempted suicide
Rare (less than 0.1%): Excitement[Ref]

Renal

Very rare (less than 0.01%): Kidney calculus[Ref]

Respiratory

Common (1% to 10%): Respiratory depression, hypoventilation, dyspnea, bradypnea, feeling of pressure in the chest[Ref]

Some side effects of Lioresal Intrathecal may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.